Osteonecrosis of the jaw (ONJ) is an emerging condition that has been associated with bisphosphonate use, typically in the context of cancer treatment. Currently, it is unknown what role, if any, bisphosphonates play in the regulation of ONJ. As of yet there are no accepted models of ONJ. However, several mechanisms have been proposed to describe a causing role for bisphosphonates in the disease. High local bisphosphonate concentration in the mandible due to enhanced drug delivery or enhanced drug retention may amplify anti- osteoclastic effects of bisphosphonates compared to non-affected skeletal sites. This may interfere with bone remodeling required following tooth removal- typically a preceding event in ONJ. Alternatively, high local bisphosphonate release from mandibular sites may lead to direct toxicity and damage to mucosal and epithelial tissues, potentially leading to local necrosis. Proper design of models for ONJ requires an understanding of whether the mandible represents an anatomic site prone to high or low local bisphosphonate concentration. The ASBMR task force on ONJ has identified the examination of bisphosphonate bioavailability and biodistribution as a key research question for the disease. Therefore, the purpose for this proposal is to quantify the delivery and retention of bisphosphonates in the mandible compared to other non-affected skeletal sites using near-infrared fluorescent imaging compounds validated by our lab as tracer markers for local bisphosphonate concentration. The central premise of this proposal is that the mandible represents a unique skeletal location that promotes high bisphosphonate concentration per bone surface area when compared to limbs not associated with ONJ. Bisphosphonate delivery and retention will be assessed under normal, low, and high bone turnover conditions using a far-red fluorescent pamidronate imaging compound to visualize local bisphosphonate concentration. Fluorescence per bone surface area will be assessed in the mandible, femur, and tibia, and correlated with local levels of bone turnover to determine the role of turnover in the delivery, and subsequent retention or clearance of drug. Findings from this proposal will clarify whether the local physiology of the jaw predisposes it to high concentrations of bisphosphonate through increased delivery or high retention, and will generate data suggesting whether drug holidays are effective, or can be boosted through relevant strategies designed to clear local bisphosphonate concentration. By determining the factors governing bisphosphonate concentration in the skeleton, these data can define important parameters and experimental questions for the development and application of accurate and valid future models for ONJ. PUBLIC HEALTH RELEVANCE: Osteonecrosis of the jaw (ONJ) is an detrimental condition of exposed bone in the oral cavity for which there are currently no accepted models for study. This proposal will determine how local bone turnover is responsible for the delivery and retention of bisphosphonates in the skeleton, and whether anatomic differences may predispose the mandible to high local bisphosphonate concentration-a potential risk factor for ONJ. It is expected that data from this proposal will define important parameters and experimental questions for the development and application of accurate and future models of ONJ.